The UDPG (uridine-diphosphoglucose) composition has been known for some time. It has been in use in Italy for 20 years. Methods for its synthesis are disclosed. U.S. Pat. No. 3,787,392 issued to Bergmeyer et al. shows synthesis of UDPG from UMP (U-5'-MP). This is a chemical process using dicyclohexyl carbodiimide (DCC) to esterify UMP to yield UDPG. Another chemical process for UDPG by Bergmeyer et al. is shown in U.S. Pat. No. 3,803,125 where UDPG (examples 4-6) is formed from U-5'-MP amidate ester compounds.
U.S. Pat. No. 3,725,201 to Sugimori et al. describes the process of obtaining UDPG by yeast action from U-5'-MP and glucose. (bottom Col. 2--top Col. 3). U.S. Pat. No. 3,717,547 to Nakayama et al. describes a bacterial fermentation process for production of UDPG from orotic acid or uracil.
5-phosphoribosyl pyrophosphate (PRPP) is a necessary metabolic intermediate in the synthesis of purine and pyrimidine nucleotides as well as other important molecules. Perturbation of the intracellular level of PRPP has been found to be relevant to the origin of certain metabolic diseases (Balis M. E., (1976) Adv. Clin. Chem. 18:213; Kelley, W. N., (1974) A. Meister, ed. 14:1). The inhibitory activity of several antimetabolites requires reaction with PRPP and therapeutic efficacy may depend on the level of PRPP in target cells relative to normal host tissues (Higuchi, T., et al. (1976) Cancer Res. 36:3779; Danks, M. K. et al. (1979) Biochem. Pharmacol. 28:2733). Higuchi et al, supra show PRPP availability to convert the anti-carcinogenic purine drug 6-MP to IMP.
U.S. Pat. No. 4,297,347 of Katsunuma shows 3'-polyphosphate pyrimidine nucleoside activity against leukemia in mice. U.S. Pat. No. 4,141,972 of Nishino et al. deals with mixed 5' and 3' (2') phosphates of purine nucleosides with anti-leukemic activity in mice.
Ardalan et al. in Biochem Pharm 31:1509 (1982) show an increase in PRPP levels in tumor-bearing animals given certain L-glutamine antagonist drugs-DON, azaserine and AT-125 [6-diazo-5-oxo-L-norleucine (DON)]. Also, 5-FU is reported therein as active in combination with methotrexate (P1513) and therefore DON, and AT-125 could be used instead of methotrexate in combination with 5'FU to increase the PRPP pool and direct 5-RU to nucleotides.
PRPP is formed by the interaction of ATP and ribose 5-phosphate (R-5-P) catalyzed by the enzyme PRPP synthetase. R-5-P is related to glucose metabolism by the pentose phosphate shunt. Alteration in glucose metabolism, as seen in glycogen storage disease Type I, has been found to increase the PRPP level in affected cells (Kelley, W. N. et al. (1974) Supra). Methylene blue stimulates the oxidative pentose phosphate pathway and concurrently increases the PRPP availability in chick liver slices (Lipstein, B., et al. (1984) Biochim. Biophys. Acta. 521:45). These findings seem to suggest that R-5-P concentrations is not saturating for intracellular PRPP production and the availability PRPP is directly related to purine synthesis.
UDPG is known to have multiple effects on intrahepatic bilirubin metabolism which in turn are related to the glycogen synthesis occurring in the liver (Casciarri, I. et al. (1977) Accademia Medica Lombarda 32:223). The precise mechanism of these interactions is not clearly defined, but it is believed that UDPG is involved in the induction of various enzymes including some active in carbohydrate metabolism (Okolicsanyi, L., et al. (1973) Enzyme 14:366). PRPP occupies an essential role in intermediary metabolism. It is required in the purine and pyrimidine biosynthetic and recycling pathways. PRPP is formed in cells by the reaction of ATP and ribose-5-phosphate by the catalytic action of PRPP synthetase. Perturbation of the level of PRPP in cells has been found to be related to many severe metabolic disturbances including Glycogen Storage Disease Type I (Balis, M. E., (1976) Adv. Clin, Chem. 18:213; Kelley, W. N., (1974) A. Meister, ed. 14:1).